The overall goal of this research plan is to elucidate how focal ischemic brain injury alters the regulation of neural stem cells in the adult forebrain sub-ventricular zone (SVZ). Advances over the past 3 decades firmly establish the persistence of neural stem cells and neurogenesis in the adult mammalian rostral SVZolfactory bulb pathway, a system that offers a potential source for neuronal replacement after brain injury or degeneration. However, the normal regulation of neurogenesis and the endogenous SVZ neural precursor response to brain injury in the adult are poorly understood. Knowledge of neurogenic mechanisms in the normal and injured mature brain is essential for developing novel therapies using endogenous or transplanted neural stem cells. We have recently discovered that focal ischemia increases neurogenesis in the adult rat rostral SVZ. Moreover, a sub-population of the newly generated neurons migrates toward damaged areas, suggesting that factors produced by injury influence the proliferation and migration of endogenous precursors. Based on these findings, the primary hypothesis of the proposed research is that forebrain SVZ neural stem cells respond to focal ischemic injury of the mature brain by generating increased numbers of new neurons that migrate toward sites of damage, survive, and integrate into residual networks. The secondary hypothesis is that specific growth factors or chemotropic guidance cues, produced normally or induced by injury, influence the proliferation and migration of neuronal precursors generated in the postnatal forebrain SVZ. The Specific Aims are: 1) To characterize the cell proliferation, migration, differentiation and integration of rostral SVZ neural precursors in the normal adult rat brain and after focal ischemic injury, 2) to determine the molecular factors that regulate rostral SVZ neuronal precursor proliferation and migration in the intact rodent brain or after ischemic injury; and 3) to determine the effects of delayed basic fibroblast growth factor (bFGF) or insulin-like growth factor1 (IGF1) administration on adult forebrain SVZ neurogenesis, and on ischemiainduced neurogenesis and infarct size after focal ischemic injury. The experimental design includes mitotic labeling and cell fate analysis of in vivo SVZ neurogenesis in the normal adult rat and in an adult rat transient-focal ischemia/stroke model, as well as studies of in vitro neurogenesis in slice cultures of the neonatal SVZolfactory bulb pathway. Progress in these Aims will advance our understanding of adult SVZ neurogenesis in the normal and ischemic brain, and may provide insight into the potential use of neural stem cells for stroke therapy.